The present invention relates to a method and apparatus for dispensing each of two or more feeds into a plurality of vessels.
In many industrial and laboratory applications, it is common to combine two or more ingredients during the course of processing or fabrication operations. In laboratory applications, the ingredients are typically combined in receiver (e.g., flask, test tube, wells in a microtitre plate, etc.) in precise proportions and under selected conditions.
In some applications, such as in the development of polymers, the manner in which the ingredients are combined is important. For example, it is often desirable or necessary for the ingredients to be simultaneously added to the receiver. In some cases, this is necessary to prevent undesired reactions from occurring.
In the development of polymers, as well as many other products (e.g., pharmaceuticals, nutraceuticals, cosmeceuticals, etc.), a preference exists for delivery systems that are capable of rapidly and efficiently producing and/or screening samples. This high-speed capability, which hastens development efforts, is commonly referred to as xe2x80x9chigh-throughput screening,xe2x80x9d xe2x80x9chigh-throughput experimentation,xe2x80x9d or xe2x80x9chigh-throughput testing,xe2x80x9d or by the respective acronyms xe2x80x9cHTS,xe2x80x9d xe2x80x9cHTE,xe2x80x9d or xe2x80x9cHTTxe2x80x9d (these monikers are synonymous). An HTE-capable ingredient delivery system must be able to provide multiple copies or multiple permutations of a sample.
FIG. 1 depicts a typical HTE-capable delivery system for creating mixtures of ingredients for the development of polymers or other products. System 100 is able to simultaneously combine three ingredients, in specific proportions, to produce a mixture F (or permutations thereof) in each of three receivers 112-A, 112-B, and 112-C (collectively xe2x80x9creceivers 112xe2x80x9d). A HTE-capable system more typically includes a minimum of eight, and more likely 12, 16 or 24 receivers. But for the purpose of simplifying FIG. 1 and the accompanying discussion, only three receivers are depicted.
System 100 includes reservoirs 102-1, 102-2, and 102-3 (collectively xe2x80x9creservoirs 102,xe2x80x9d) which contain respective ingredients I-1, I-2, I-3 (collectively xe2x80x9cingredients Ixe2x80x9d). The reservoirs are maintained under positive pressure, via pressurized gas source 104, so that the ingredients I can be delivered to receivers 112.
Each reservoir 102 has three conduits 106 that lead to three valves 108. The three valves, in turn, feed the three receivers 112. With this arrangement, the ingredient I in a given reservoir 102 can be delivered to each of the three receivers 112-1, 112-2, and 112-3.
More particularly, and with respect to reservoir 102-1, one of conduits 106-1 connects that reservoir to valve 108-A1, another of conduits 106-1 connects reservoir 102-1 to valve 108-B1, and the third conduit 106-1 connects reservoir 102-1 to valve 108-C1. With respect to reservoir 102-2, one of conduits 106-2 connects that reservoir to valve 108-A2, another of conduits 106-2 connects that reservoir to valve 108-B2, and the third conduit 106-2 connects reservoir 102-2 to valve 108-C2. And, with respect to reservoir 102-3, one of conduits 106-3 connects that reservoir to valve 108-A3, another of conduits 106-3 connects that reservoir to valve 108-B3, and the third conduit 106-3 connects reservoir 102-3 to valve 108-C3.
As follows from the foregoing description, and as indicated in FIG. 1, each receiver 112 is served by three valves. Specifically, valves 108-A1, 108-A2, 108-A3 control the flow of respective ingredients I-1, I-2, I-3 into receiver 112-A. Similarly, valves 108-B2, 108-B2, 108-B3 control the flow of respective ingredients I-1, I-2, I-3 into receiver 112-8 and valves 108-C1, 108-C2, 108-C3 control flow of respective ingredients I-1, I-2, I-3 into receiver 112-C.
Valves 108, which can be proportional valves, or which are otherwise time or flow controlled, are capable of providing precise control over parameters such as flow pressure, flow rate and the like. Open or closed-loop control systems are typically associated with each valve to ensure that the proper amount of each ingredient is delivered to each receiver 112.
System 100 depicts a classic, combinatorial-type, liquid-dispensing arrangement. The combinatorial-type arrangement enables all ingredients I (i.e., I-1, I-2, I-3) to be delivered simultaneously to all receivers 112 (i.e., 112-1, 112-2, and 112-3).
A drawback of the combinatorial-type of arrangement is that for a delivery system having n reservoirs (for I ingredients, where Ixe2x89xa6n) and m receivers, nxc3x97m valves are required. For example, a system having five reservoirs and sixteen receivers requires eighty valves, which is an expensive proposition. Furthermore, the large number of valves can cause reliability issuesxe2x80x94a problem with any one of the eighty valves will require shutdown of the system. Furthermore, the large number of intermediate valves and fluidic channels increases the likelihood of cross-contamination (e.g., due to inadequate cleaning between uses, etc.), precipitation of solids within the valves and channels, and other problems.
So, a problem presents itself. When creating mixtures in which all ingredients must be combined at substantially the same time, or in which multiple copies of the mixture or variations of it must be created at the substantially the same time, how can the equipment-intensive arrangements of the prior art be avoided?
A HTE-capable delivery system and method for combining ingredients that solves the problem that is posed above and that avoids some of the drawbacks of the prior art is disclosed.
In accordance with the invention, and unlike prior-art combinatorial-type systems, ingredients are delivered in pulses to receivers. Each pulse contains only a minor portion of the total amount of ingredient to be dispensed. In the illustrative embodiment, ingredients are delivered individually (not pre-mixed with any other ingredient), although this is not a requirement of the method or the system.
In some embodiments, the pulses are sequenced so that each ingredient is added to all the receivers in a very short period of time. As a consequence of this sequencing:
any one ingredient is added to all of the receivers at nearly the same time;
when multiple ingredients are added to a receiver, they are added at nearly the same time;
mixtures formed in each receiver are formed at about the same time; and
successive drops of a particular ingredient are dispensed into a particular receiver at nearly the same time.
This provides a capability of forming mixtures for which all ingredients must be added at nearly the same time. And because the dispensing operation is pulsed and sequenced, the dispensing system that is used to dispense the ingredients can have conduits that do not directly couple to a receiver (unlike prior-art combinatorial-type delivery systems; see FIG. 1). A system in accordance with the illustrative embodiment of the present invention can, therefore, be substantially less equipment intensive than prior-art combinatorial-type delivery systems.
In particular, some variations of the illustrative system have only one dispensing element (e.g., valve, nozzle, orifice, tube, etc.) per ingredient dispensed, irrespective of the number of receivers in the system. Consequently, a five-reservoir dispenser in accordance with the illustrative embodiment that dispenses into sixteen receivers uses only five dispensing elements, as compared to eighty for some prior-art arrangements.
An ancillary benefit of pulsed dispensing is that since each pulse of ingredient delivered to a receiver contains substantial kinetic energy, some degree of mixing occurs without using an external mixer.
In some embodiments of a delivery system in accordance with the illustrative embodiment of the present invention, the dispensing elements are moved into aligned with the receivers to dispense ingredients. Delivery systems having dispensing elements that move to receivers, or receivers that move to dispensing elements are known in the art. In operation, these prior-art dispensers are typically operated to deliver a full charge of liquid ingredient to a first receiver vessel, and then fill others vessels, seriatim. But, as a consequence of their programming and other limitations, these dispensers cannot be used for applications wherein multiple ingredients, which cannot be pre-mixed with one another, are added to a plurality of receivers at nearly the same time, and with adjustable ratio control of ingredient flow.
The incremental, pulse-wise addition of ingredients described herein is performed in such a way that, from the xe2x80x9cperspectivexe2x80x9d of the mixture being formed, the ingredients are added quasi-continuously or quasi-simultaneously or both. These terms have a particular meaning for use in this specification, and are explicitly defined in the xe2x80x9cDetailed Descriptionxe2x80x9d section below. But by way of introduction, the term xe2x80x9cquasi-continuousxe2x80x9d means that the addition of an ingredient to a receiver is considered to be substantially continuous from the xe2x80x9cperspectivexe2x80x9d of the mixture being formed. And one meaning of the term xe2x80x9cquasi-simultaneousxe2x80x9d is that all ingredients are added to a receiver at substantially the same time from the xe2x80x9cperspectivexe2x80x9d of the mixture being formed. The significance of the phrase xe2x80x9cfrom the perspective of the mixturexe2x80x9d is that the actual addition of ingredient can be rapid or slow, as a function of the nature of the mixture.
A delivery system in accordance with the invention includes a system controller, a drive system and a dispensing system. Using information about the drive system, the dispensing system, the receivers, and the mixture being formed, the system controller is capable of:
determining an execution sequence in accordance with a dispensing protocol;
causing the drive system to align, on an ongoing basis, the dispensing system and the receivers in accordance with the execution sequence; and
causing the dispensing system to dispense ingredients into each of the receivers in accordance with the execution sequence.
The dispensing protocol dictates that:
ingredients are dispensed in a plurality of pulses, wherein each pulse contains a minor fraction of the total quantity of ingredient to be dispensed within a selected time interval; and
dispensing is quasi-continuous; or
dispensing is quasi-simultaneous; or
dispensing is quasi-continuous and quasi-simultaneous.
In some embodiments, determining the execution sequence comprises:
determining the speed (which can be varied during the operation) at which the dispensing system and receivers are moved relative to one another (although in other embodiments, the relative movement is intermittent);
determining the quantity of ingredient delivered during each pulse (which can be varied during the operation), per ingredient, per receiver; and
determining the time sequencing of pulses, per ingredient.
In some embodiments, when the proportions of the various ingredients that compose a mixture are similar (e.g., 1:1.1:0.9:1.2:1, etc.), a small amount of each ingredient will typically be dispensed into a given receiver before that receiver gets xe2x80x9csecondsxe2x80x9d of any particular ingredient. After all the receivers receive a small amount of each ingredient (via a pulse from each dispensing element), a first dispensing cycle is completed. A second cycle then follows without interruption, wherein each of the receivers gets a second pulse of one or more of the ingredients.
When there are substantial imbalances in the proportions of the various ingredients that compose the mixture (e.g., 1:1:1:1:0001, etc.), it might be advantageous not to deliver minor ingredients in some dispensing cycles because of the difficulty of accurately dispensing such small quantities of liquid. As a consequence of skipping cycles, a greater quantity of the ingredient will be dispensed when the pulse occurs. As an alternative, lower flow-rate valves can be used for minor ingredients so that it is not necessary to skip dispensing cycles.
The drive system of the quasi-continuous dispenser can be configured in a variety of ways. For example, in one implementation, the drive system includes a gantry that is rapidly positionable in one or more directions. The gantry positions the dispensing system, which includes one or more dispensing elements, over the receivers. Once positioned, at least one of the dispensing elements in the system dispenses, via a pulse, a small amount of an ingredient into a receiver. The dispensing system is then rapidly repositioned, under the control of the system controller, enabling the same or different ingredients to be dispensed into the same or different receivers. The dispensing operation continues, under the control of the system controller, until the required delivery profile for each ingredient is satisfied.
In another implementation, a rotary drive system is used. The rotary drive system has a higher throughput than a gantry-based drive system and avoids the potentially problematic, rapid, reciprocating motion of the gantry-based drive system. Gantry-type motion results in the xe2x80x9cFILOxe2x80x9d (First In Last Out) problem, wherein after the last dispense within a cycle, the gantry must be returned to its original position to start a subsequent cycle.
In some embodiments, the rotary drive system includes at least one arm (more typically two to six arms) that is positioned over a plurality of receivers. The arm, which in the illustrative embodiment is capable of being rapidly rotated, advantageously includes at least one dispensing element that dispenses an ingredient into the receivers.
A rotary dispenser that incorporates a rotary drive system and that is suitable for use in conjunction with the present invention is described in applicants""co-pending application entitled xe2x80x9cRotary-Drive Dispenser,xe2x80x9d filed on even date herewith as Ser. No. 60/441,757 and incorporated by reference herein.
Regardless of dispenser configuration, it is advantageous (but not necessary) to incorporate analytical testing capabilities into the delivery system. Preferably, on-line samples are taken from receivers as the mixtures are being produced. One or more test(s) are performed on the samples using one or more test stations. Test results can then be sent to the system controller to close a control loop. That is, based on the test results, the system controller can modify the dispensing protocol (e.g., amount of ingredient delivered per pulse length, pulse frequency, etc.) as required to keep the mixtures on specification.
To that end, some variations of the illustrative system incorporate an analysis station, such as the analysis station described in the Rotary-Drive Dispenser application referenced above. One of these analysis stations is capable of performing at least one type of analysis on the mixtures being produced in each of the receivers.
Often, the amount of an ingredient that is contained in each dispensing pulse is quite small (typically in the range of nanoliters to microliters). Consequently, the delivery system is advantageously capable of accurately dispensing very small quantities of liquid to avoid inaccuracies in the mixtures. Since most valves have limited life expectancy when dispensing such small liquid quantities (at a high-frequency of operation), it is advantageous to use a valve-less dispensing system. Some variations of the illustrative delivery system therefore incorporate a valve-less dispensing element, as can be implemented using a nozzle described in applicant""s co-pending application entitled xe2x80x9cRotary-Drive Dispenser,xe2x80x9d referenced above.
These and other variations of a delivery system and method in accordance with the illustrative embodiment of the present invention are illustrated in the Drawings and described further in the Detailed Description section of this specification.
The following non-limiting example is provided by way of an introduction to the concepts of (1) quasi-continuous dispensing; (2) quasi-simultaneous dispensing; (3) the significance of pulsed delivery of ingredients; and (4) as an example of a use for the illustrative method and delivery system.
Four ingredients are to be delivered from a delivery system having four dispensing elements, one ingredient from each dispensing element. The ingredients are to be delivered to four receivers to create four identical mixtures. The receivers are aligned in a circular pattern. The dispensing elements are moved along a circular path over the receivers. The delivery system delivers ingredients via pulses into the receivers. A pulse lasts for 0.025 seconds, and, at any given moment, a different ingredient is delivered into each of the four receivers. The dispensing elements are being moved at a rate of one revolution per 0.5 seconds (i.e., in one revolution, each dispensing element passes over all four receivers).
In operation, in the first 0.025 seconds, one pulse of ingredient is dispensed into each receiver, with a different ingredient being dispensed into each receiver. For example, a pulse of ingredient xe2x80x9cAxe2x80x9d is dispensed into receiver xe2x80x9c1,xe2x80x9d a pulse of ingredient xe2x80x9cBxe2x80x9d is dispensed into receiver xe2x80x9c2,xe2x80x9d and so forth. The full pulse is delivered to each receiver before the dispensing element is out of dispensing range of that receiver. As each element passes into range of the next receiver, a second pulse of ingredient is delivered, one ingredient per receiver. So, after these two pulses, each receiver contains one pulse of each of two ingredients. For example, one pulse of ingredient xe2x80x9cAxe2x80x9d and one pulse of ingredient xe2x80x9cDxe2x80x9d has been added to receiver xe2x80x9c1xe2x80x9d and one pulse of ingredient xe2x80x9cBxe2x80x9d and one pulse of ingredient xe2x80x9cAxe2x80x9d has been added to receiver xe2x80x9c2.xe2x80x9d
Pulsed dispensing continues. After one complete revolution, each receiver contains one pulse of each of the four ingredients. The time elapsed is 0.5 seconds. Thus, in 0.5 seconds, any given receiver contains a small quantity of each of the four ingredients (xe2x80x9cthe mixturexe2x80x9d), and each receiver contains the same small amount of the mixture. These are both attributes of what is meant by xe2x80x9cquasi-simultaneousxe2x80x9d dispensing.
Soon after completing the first revolution, each dispensing element is in range to deliver a second pulse of an ingredient to the receiver into which they first dispensed that ingredient. Thus, the second pulse of ingredient xe2x80x9cAxe2x80x9d is delivered to receiver xe2x80x9c1,xe2x80x9d the second pulse of ingredient xe2x80x9cBxe2x80x9d is delivered to receiver xe2x80x9c2,xe2x80x9d and so forth. Since the first cycle was completed after 0.5 seconds, the second pulse of each ingredient is delivered by 0.5025 seconds. The rate, in this case a relatively rapid rate, at which successive pulses of an ingredient are received by a particular receiver is an attribute of xe2x80x9cquasi-continuousxe2x80x9d dispensing. That is, with a particular ingredient being dispensed into a particular receiver at a rate of one pulse each 0.5 seconds, the dispensing is nearly continuous or xe2x80x9cquasixe2x80x9d continuous.
It is to be understood that this Example is provided by way of introduction to the concepts of quasi-continuous dispensing and quasi-simultaneous dispensing, as described herein, and should not be considered as a limitation on the application of these concepts. In particular, an important aspect of these concepts is that they are defined relative to a mixture being created. That is, as a function of the properties of the ingredients and the mixture, quasi-continuous dispensing and quasi-simultaneous dispensing can correspond to a very slow actual rate of dispensing of ingredients into receivers.
Also, in Example I, the length of each pulse (and hence the amount of ingredient delivered) is assumed to be invariant from pulse to pulse and to be the same for each ingredient. But as desired, the length of a pulse can be varied from pulse-to-pulse and from ingredient-to-ingredient.
Furthermore, in many applications, the composition of the mixtures being formed will vary from one receiver to the next (e.g., by changing the amount of one ingredient, etc.), rather than being identical as in the Example. Also, in some embodiments, more than one pulse of an ingredient is delivered to a particular receiver before any pulses of that ingredient are received by any of the other receivers. Further, the timing between pulses can vary.
These and other variations on the concepts of quasi-continuous dispensing and quasi-simultaneous dispensing, and their application to the creation of mixtures, will be described later in this specification.